WO2016070834A1 - 含有细胞周期蛋白抑制剂的药物制剂及其制备方法 - Google Patents
含有细胞周期蛋白抑制剂的药物制剂及其制备方法 Download PDFInfo
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- WO2016070834A1 WO2016070834A1 PCT/CN2015/093953 CN2015093953W WO2016070834A1 WO 2016070834 A1 WO2016070834 A1 WO 2016070834A1 CN 2015093953 W CN2015093953 W CN 2015093953W WO 2016070834 A1 WO2016070834 A1 WO 2016070834A1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims 1
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- MDZKJHQSJHYOHJ-UHFFFAOYSA-N crataegolic acid Natural products C1C(O)C(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MDZKJHQSJHYOHJ-UHFFFAOYSA-N 0.000 claims 1
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
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- AXLHVTKGDPVANO-UHFFFAOYSA-N methyl 2-amino-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)C(N)CNC(=O)OC(C)(C)C AXLHVTKGDPVANO-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical preparation for a cyclin inhibitor and a preparation method thereof.
- Cyclin-dependent kinase has 13 members, all of which belong to the serine/threonine protein kinase family. It is dependent on cyclin binding, promotes cell cycle phase transition, initiates DNA synthesis, and regulates cell transcription. And other key features.
- CDKs The critical role of CDKs in the proliferation and death of all cells, including healthy and tumor cells, is that it is difficult for a broad spectrum of CDK inhibitors, especially for patients who have not been genetically screened, to exhibit a higher therapeutic window.
- the dose is too toxic and too small to be effective. Therefore, it is particularly important to selectively suppress part of the CDK.
- CDK subtypes have relatively similar chemical structures, how to increase the selectivity of CDK inhibitors is another challenge.
- CDK4/6 as an anti-tumor target is that: 1 CDK4/6 inhibitor does not exhibit cytotoxicity of "pan-CDK inhibitor", such as myelosuppression and intestinal response; 2 cell cyclin D levels are elevated or P161NK4a is lost Live, can increase the sensitivity of cells to drugs, tumor cells have the above phenomenon relative to normal cells, so the drug targeting is increased to some extent.
- the compound of formula I is a targeted CDK4/6 inhibitor that selectively inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), restores cell cycle control, and blocks tumor cell proliferation. Its effect on MDA-MB-435 breast cancer cells can effectively reduce the phosphorylation of Rb at Ser780 and Ser795, IC50 is 66nM and 63nM, respectively.
- Breast cancer is one of the most common malignant tumors in women. It has a high incidence and is invasive, but the course of disease is slow. According to data released by the International Agency for Research on Cancer, there were approximately 1.67 million new cases worldwide in 2012, accounting for 25% of all cancers. According to the National Cancer Center's Epidemiological Survey and Final Results (SEER), the estimated prevalence of breast cancer in the United States in 2013 was 123.8 per 100,000. The incidence of breast cancer among women in the Asian population from 2005 to 2009 was 94.5 per 100,000. There is no official data in China. It is estimated that 60% to 70% of breast cancer patients in China have positive estrogen or progesterone receptors. The incidence of estrogen receptor-positive breast cancer in China from 2005 to 2009 is estimated to be 56.7 ⁇ 66.15/10. Ten thousand people. Thomson predicts that sales will increase significantly after the launch of the product, and sales in 2019 will reach $2.027 billion.
- a pharmaceutical composition comprising a compound of formula I or a salt thereof, and a pharmaceutically acceptable excipient, including a hydrochloride salt, an isethionate, and a pharmaceutically acceptable excipient.
- the compound of formula I comprises from 10% to 80%, preferably from 15% to 60%, more preferably from 20% to 40% by weight of the composition.
- the composition comprises a compound of the formula I or a salt thereof and an excipient, the excipient comprising one or more of a disintegrant, a diluent, a binder, a surfactant, a lubricant, preferably
- the weight of each component is as follows:
- composition may further comprise a flavoring agent, a coloring agent or a coating material, and most preferably, the sum of the weight percentages of the above components is 100%.
- the weight percentage of each component is as follows:
- composition may further comprise a flavoring agent, a coloring agent or a coating material, and most preferably, the sum of the weight percentages of the above components is 100%.
- the weight percentage of each component is as follows:
- the diluent is selected from at least one of starch, icing sugar, dextrin, lactose, pregelatinized starch, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, and microcrystalline cellulose, further Preferably, the diluent is selected from at least one of lactose, microcrystalline cellulose, starch or mannitol, and more preferably, the diluent is selected from the group consisting of lactose and microcrystalline cellulose.
- the weight ratio of the lactose to the microcrystalline cellulose is from 1:2 to 2:1, preferably 1:1.
- the binder is selected from at least one of starch syrup, hypromellose, hydroxypropyl cellulose, povidone, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, and the like.
- the diluent is selected from at least one of hydroxypropyl cellulose or povidone.
- the disintegrant is selected from at least one of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, dry starch, low-substituted hydroxypropylcellulose, and more preferably, The disintegrant is selected from at least one of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium.
- the lubricant is selected from at least one of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, colloidal silica, talc, and silica.
- the lubricant is selected from at least one of stearic acid, glyceryl behenate, and colloidal silica.
- the surfactant is sodium lauryl sulfate, Tween 80 and poloxamer. More preferably, the surfactant is sodium lauryl sulfate.
- the present invention provides a process for the preparation of a compound of formula (I) or a salt thereof, which comprises a process such as wet granulation, dry granulation, direct mixing, and the like, and the dosage form includes tablets and capsules.
- composition is completed by wet granulation, the method comprising the steps of:
- step (3) drying the particles of step (2) in a fluidized bed dryer or drying oven;
- step (3) optionally, drying and sieving the dried granules of step (3);
- step (4) mixing the dried granules of step (4) with the remaining excipients to obtain a final mixture
- step (6) optionally, filling the mixture of the above step (5) by a suitable capsule filling machine to prepare a capsule;
- step (7) optionally, by compressing the mixture of the above step (5) on a suitable tablet press, and compressing the sheet to obtain a core;
- the core of the step (7) is film-coated with a film coating.
- the composition is accomplished by dry granulation, the method comprising the steps of:
- step (2) compacting the mixture of step (1) in a suitable roller press
- step (4) optionally, filling the mixture of the above step (4) by a suitable capsule filling machine to prepare a capsule;
- step (6) optionally, by compressing the mixture of the above step (4) on a suitable tablet press, and compressing the sheet to obtain a core;
- the core of step (6) is film coated with a film coating.
- the present invention provides a stable, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H suitable for medical applications.
- a pharmaceutical preparation of pyrido[2,3-d]pyrimidin-7-one and a salt which has excellent dissolution behavior and good stability, meets the requirements of clinical application, and enables the active ingredient to achieve good in vivo bioavailability degree.
- Prescription 1 Prescription 2
- Prescription 3 Prescription 4
- Prescription 5 Prescription 6
- Prescription 7 Prescription 8 10min 35 40 32 27 twenty two 42 41 37 15min 62 66 68 56 55 66 69 65 30min 78 82 77 70 73 79 82 79 45min 89 91 93 83 80 87 89 83 60min 95 96 98 88 91 99 96 95
- Prescription 9 Prescription 10
- Prescription 11 Prescription 12
- Compound of formula I 75 75 100 125 Microcrystalline cellulose 38.7 10.8 93.9 117.3 lactose 54.3 18.8 49.7 65.7 Hydroxypropyl cellulose / / / 17.5
- Povidone 10.5 3.5 14 / Carboxymethyl starch sodium / 10.5 14 17.5
- the above 1000 tablets of the formula I and the excipients other than magnesium stearate are mixed into a hopper mixer, pressed into a ribbon by a roller press, the ribbon is broken into granules, and magnesium stearate is added. Total Mix for 10min, control the content, fill the capsule. Or pressed into tablets.
- Prescription 9 Prescription 10
- Prescription 12 10min 44 38 35 38 15min 69 63 64 70 30min 76 74 75 81 45min 93 90 89 90 60min 98 98 93 92
- Prescription 13 Prescription 14
- Prescription 15 Compound of formula I 75 75 75 75 Microcrystalline cellulose 71.8 / 50 lactose 35.9 25.8 15.7 Hydroxypropyl cellulose 10.5 6.0 9.0 Carboxymethyl starch sodium 10.5 6.0 5.0 Cross-linked povidone / 3.0 4.0 Sodium dodecyl sulfate 2.1 / 2.1 talcum powder 2.1 2.1 2.1 Magnesium stearate 2.1 2.1 2.1 weight 210 120 165
- Prescription 16 Prescription 17
- Prescription 18 API 2 125 125 125
- Microcrystalline cellulose 124.3 64.5 27.1 lactose 62.2 64.6 27.1 Hydroxypropyl cellulose 17.5 8.4 16.8
- Cross-linked povidone / 14 10.5 Croscone sodium 17.5 / / Magnesium stearate 3.5 3.5 3.5 weight 350 280 210
- API refers to the hydrochloride or isethionate salt of the compound of formula I.
- the above 1000 prescription API and other excipients other than magnesium stearate are put into the hopper mixer, and the wetting agent is wetted and granulated.
- the fluidized bed is dried at 45 ° C for 10 min, 1.0 mm sieve, and hardened.
- the magnesium oleate was mixed for 10 minutes, the content was controlled, and the capsule was filled. Or pressed into tablets.
- Prescription 16 Prescription 17
- Prescription 18 5min 70 73 71 15min 95 92 91 30min 98 97 98
- Prescription 19 Prescription 20
- Prescription 21 Prescription 22
- API 2 75 75
- Povidone 10.5 10.5 8.25 14
- Carboxymethyl starch sodium / 10.5 5 14
- API refers to the hydrochloride salt of the compound of formula I (Note: The above formulation is equally applicable to isethionate, and the inventors have tested that the dissolution effect is very close to that of the hydrochloride as an API).
- the above 1000 prescription API and other excipients except magnesium stearate are put into a hopper mixer, and pressed into a ribbon by a roller press, the ribbon is broken into granules, and magnesium stearate is mixed. 10min, medium control content, filling capsules. Or pressed into tablets.
- Prescription 19 Prescription 20
- Prescription 21 Prescription 22 5min 76 70 68 69 15min 99 94 97 91 30min 98 99 99 97
- Prescription 23 Prescription 24 Prescription 25 API 2 75 100 125 Microcrystalline cellulose 37.3 49.7 62.2 lactose 74.6 99.5 124.3
- API refers to the hydrochloride salt of the compound of formula I (Note: The above formulation is equally applicable to isethionate, and the inventors have tested that the dissolution effect is very close to that of the hydrochloride as an API).
- the above 1000 prescription API and excipients were mixed into a hopper mixer, and the content was controlled, and the capsule was filled. Or pressed into a plain tablet, coated, controlled coating weight gain 3%.
- Prescription 23 Prescription 24 Prescription 25 5min 62 60 59 15min 90 90 94 30min 97 95 99
- the compound of formula I corresponds to 96 mg of the compound of the formula I isethionate, and other specifications correspond to the conversion.
- Prescription 26-28 1000 tablets of prescription API and excipients are mixed into the hopper mixer, medium-controlled content, filled capsules.
- Prescription 29-30 after mixing, directly pressed into a plain tablet, coated, and controlled to increase the weight of the coating by 3%.
- Prescription 26 Prescription 27
- Prescription 28 Prescription 29
- Prescription 30 5min 40 60 82 85
- 40 15min 82 85 95 95 73
- 30min 97 100 103 98 99
- Prescription 31 Prescription 32
- Prescription 33 Prescription 34
- Compound of formula I 75 100 100 125 125 Microcrystalline cellulose 86.7 77.1 154.1 144.5 56.3 lactose 86.7 154.1 77.1 144.5 232.7 Carboxymethyl starch sodium 13.5 18 18 22.5 22.5 Colloidal silica 5.4 7.2 7.2 9.0 9.0 Magnesium stearate 2.7 3.6 3.6 4.5 4.5 weight 270 360 360 450 450
- Prescription 31-32 1000 tablets of prescription API and excipients are mixed into the hopper mixer, medium-controlled content, filled with capsules.
- Prescription 33-34 after mixing, directly pressed into a plain tablet, coated, and controlled to increase the weight of the coating by 3%.
- Formula 35 mixing the compound of the formula I and other excipients other than magnesium stearate into a hopper mixer, pressing into a ribbon by a roller press, crushing the ribbon into granules, and adding magnesium stearate to the mixture. 10 min, medium control content, pressed into tablets, coated, controlled coating weight gain 3%.
- Prescription 31 Prescription 32
- Prescription 33 Prescription 34
- Prescription 35 5min 85 77 76 83 70 15min 94 85 91 95 85 30min 98 100 97 99 99
- Example 8 The capsule prepared in Example 8 was placed in a commercially available package at 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5% for 6 months. The test results are shown in Table 1.
- Prescription 36 Prescription 37
- Prescription 38 Prescription 39
- Prescription 40 Prescription 41 Salts of compounds of formula I 1 81 81 81 160 160 160
- Microcrystalline cellulose 101 67.5 135 100 56.5 33 lactose 101.5 135 67.5 37.5 56.5 66 starch / / / / / / Hydroxypropyl cellulose / / / / 17.5 17.5
- the compound of the formula I and the external excipient of the lubricant are subjected to wet granulation, dried, and then granulated, and the lubricant is added for 10 minutes, and the content is controlled.
- Prescription 36 Prescription 37
- Prescription 38 Prescription 39
- Prescription 40 Prescription 41 5min 85 79 77 65 56 50 15min 95 89 90 79 80 76 30min 102 96 97 94 93 94
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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US15/524,394 US20180280392A1 (en) | 2014-11-07 | 2015-11-06 | Pharmaceutical preparation comprising cyclin inhibitor and preparation method thereof |
EP15857367.5A EP3216450B1 (en) | 2014-11-07 | 2015-11-06 | Pharmaceutical preparation comprising cyclin inhibitor and preparation method thereof |
CN201580043546.8A CN106794183B (zh) | 2014-11-07 | 2015-11-06 | 含有细胞周期蛋白抑制剂的药物制剂及其制备方法 |
JP2017521077A JP6682739B2 (ja) | 2014-11-07 | 2015-11-06 | サイクリン阻害剤を含有する医薬製剤およびその製造方法 |
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CN201410623810.2A CN105616418A (zh) | 2014-11-07 | 2014-11-07 | 含有细胞周期蛋白抑制剂的药物制剂及其制备方法 |
CN201410623810.2 | 2014-11-07 |
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US (1) | US20180280392A1 (ja) |
EP (1) | EP3216450B1 (ja) |
JP (1) | JP6682739B2 (ja) |
CN (2) | CN105616418A (ja) |
TW (1) | TWI704918B (ja) |
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CN110314148A (zh) * | 2019-05-07 | 2019-10-11 | 安徽金太阳生化药业有限公司 | 一种磷酸氢钙片的制备方法 |
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US10449195B2 (en) | 2016-03-29 | 2019-10-22 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
WO2022063119A1 (zh) * | 2020-09-24 | 2022-03-31 | 南京济群医药科技股份有限公司 | 一种羟乙磺酸哌柏西利的组合物及药物 |
CN114306245A (zh) | 2020-09-29 | 2022-04-12 | 深圳市药欣生物科技有限公司 | 无定形固体分散体的药物组合物及其制备方法 |
CN117298115A (zh) * | 2022-11-18 | 2023-12-29 | 轩竹生物科技股份有限公司 | CDKs抑制剂的药物组合物及制备方法 |
Citations (3)
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CN101001857A (zh) * | 2002-01-22 | 2007-07-18 | 沃尼尔·朗伯有限责任公司 | 2-(吡啶-2-基氨基)-吡啶并[2,3-d]嘧啶-7-酮 |
CN104892604A (zh) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | 一种新型的cdk4抑制剂的合成方法 |
CN105213322A (zh) * | 2015-10-30 | 2016-01-06 | 南京正大天晴制药有限公司 | 一种干法制粒工艺制备的药物组合物 |
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US20010007863A1 (en) * | 1998-06-18 | 2001-07-12 | Merck & Co., Inc. | Wet granulation formulation for bisphosphonic acids |
EP1648889B1 (en) * | 2003-07-11 | 2008-10-29 | Warner-Lambert Company LLC | Isethionate salt of a selective cdk4 inhibitor |
WO2008057267A2 (en) * | 2006-10-27 | 2008-05-15 | Fmc Corporation | Co-processed microcrystalline cellulose and sugar alcohol as an excipient for tablet formulations |
TW201129386A (en) * | 2009-11-05 | 2011-09-01 | Fmc Corp | Microcrystalline cellulose and calcium phosphate compositions useful as pharmaceutical excipients |
DK2958916T3 (en) * | 2013-02-21 | 2018-11-12 | Pfizer | Solid forms of a selective CDK4 / 6 inhibitor |
EP3186252A1 (en) * | 2014-08-28 | 2017-07-05 | ratiopharm GmbH | Method of producing palbociclib and pharmaceutical compositions comprising the same |
KR102068423B1 (ko) * | 2015-06-04 | 2020-01-20 | 화이자 인코포레이티드 | 팔보시클립의 고체 투여 형태 |
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- 2015-11-06 US US15/524,394 patent/US20180280392A1/en not_active Abandoned
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CN101001857A (zh) * | 2002-01-22 | 2007-07-18 | 沃尼尔·朗伯有限责任公司 | 2-(吡啶-2-基氨基)-吡啶并[2,3-d]嘧啶-7-酮 |
CN104892604A (zh) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | 一种新型的cdk4抑制剂的合成方法 |
CN105213322A (zh) * | 2015-10-30 | 2016-01-06 | 南京正大天晴制药有限公司 | 一种干法制粒工艺制备的药物组合物 |
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Cited By (1)
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CN110314148A (zh) * | 2019-05-07 | 2019-10-11 | 安徽金太阳生化药业有限公司 | 一种磷酸氢钙片的制备方法 |
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EP3216450A4 (en) | 2018-06-13 |
CN106794183A (zh) | 2017-05-31 |
CN106794183B (zh) | 2021-06-18 |
EP3216450B1 (en) | 2021-09-22 |
JP2017532347A (ja) | 2017-11-02 |
EP3216450A8 (en) | 2018-02-07 |
US20180280392A1 (en) | 2018-10-04 |
TW201617082A (zh) | 2016-05-16 |
TWI704918B (zh) | 2020-09-21 |
EP3216450A1 (en) | 2017-09-13 |
JP6682739B2 (ja) | 2020-04-15 |
CN105616418A (zh) | 2016-06-01 |
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